The overall objective of our proposed research is to discover a PPARg-free thiazolidinedione (TZD) which shows antidiabetic activity in a rodent model of Type 2 diabetes and demonstrates the necessary drug-like qualities to become a clinical candidate for human therapeutics. The insulin sensitizing agents of the TZD class are conventionally thought to operate through binding to PPARg receptors. However, strong evidence has also been gathered to show that undesirable side effects of TZDs are mediated through PPARg binding. Moreover, it has recently been suggested that rosiglitazone, the prototypical PPARg activator, could have some untoward acute cardiovascular effects. Contrary to the prevailing scientific view, the investigators of this proposal believe that non-PPAR mediated mechanisms are responsible for the insulin sensitizing pharmacology. There is a critical need to challenge the status quo with the goal of finding com- pounds that might be useful in the treatment of diabetes. In this Fast Track STTR application, the Metabolic Solutions Development Company (MSD) proposes to build on its knowledge of PPARg-sparing TZDs and expand to a PPARg-free analog series;to evaluate the antidiabetic activity of the analogs in a rodent model of Type 2 diabetes;and to evaluate the drug-like properties (pharmacokinetics, bioavailability, preliminary toxicology) that are important in further clinical development. Our hypothesis is that the insulin sensitization occurs though mitochondrial effects of the TZDs at least partly through binding to a novel mitochondrial target protein, mitoNEET. Our academic collaborators at UCSD have further characterized mitoNEET as an Fe-S protein important to mitochondrial function. The current proposal will transfer technology from UCSD to allow MSD to optimize PPARg-free analogs for treatment of Type 2 diabetes. The ultimate goal of this project is to identify a candidate PPAR3- free TZD that can be submitted to a STTR Phase III program which will require additional IND- driven preclinical evaluation. A successful candidate would then undergo clinical testing and would have the potential to be commercialized for treatment of Type 2 diabetes. PUBLIC HEALTH RELEVANCE: The incidence of type 2 diabetes is reaching epidemic proportions in our society. This proposal will provide insight into the mechanism of action of a major class of drugs used in the treatment of diabetes, called thiazolidinediones, which have undesirable side effects. It is the intent of the project to identify a new sub-class of thiazolidinediones for treatment of diabetes that are free of these undesirable side effects.